Cardiovascular disease (CVD) is the most common disease to increase as life expectancy increases. Most high-profile pharmacological treatments for age-related CVD have led to inefficacious results, implying that novel approaches to treating these pathologies are needed. Emerging data have demonstrated that senescent cardiovascular cells, which are characterized by irreversible cell cycle arrest and a distinct senescence-associated secretory phenotype, accumulate in aged or diseased cardiovascular systems, suggesting that they may impair cardiovascular function. This review discusses the evidence implicating senescent cells in cardiovascular ageing, the onset and progression of CVD, and the molecular mechanisms underlying cardiovascular cell senescence. We also review eradication of senescent cardiovascular cells by small-molecule-drug-mediated apoptosis and immune cell-mediated efferocytosis and toxicity as promising and precisely targeted therapeutics for CVD prevention and treatment. The National Cancer Institute's Radiation Research Program in collaboration with the Radiosurgery Society hosted a workshop on Understanding High-Dose, Ultra-High Dose rate and Spatially Fractionated Radiotherapy on August 20-21, 2018 to bring together experts in experimental and clinical experience in these and related fields. Critically, the overall aims were to understand the biological underpinning of these emerging techniques and the technical/physical parameters that must be further defined to drive clinical practice through innovative biologically-based clinical trials. PURPOSE We examined the capacity of the pan-fibroblast growth factor receptor (FGFR) inhibitor AZD4547 to augment radiation response across a panel of head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts. https://www.selleckchem.com/products/nutlin-3a.html EXPERIMENTAL DESIGN FGFR1, FGFR2, FGFR3 RNA in situ hybridization (ISH) expression was assessed in a cohort of HNSCC patient samples, cell lines and patient-derived xenografts (PDXs). In vitro effects of AZD4547 and radiation on cell survival, FGFR signaling, apoptosis, autophagy, cell cycle and DNA damage repair were evaluated. Reverse phase protein array (RPPA) was used to identify differentially phosphorylated proteins in cells treated with AZD4547. In vivo tumor responses were evaluated in cell line and PDX models. RESULTS FGFR1, FGFR2 and FGFR3 RNA ISH were expressed in 41%, 81% and 89%, of 107 oropharynx patient samples. Sensitivity to AZD4547 did not directly correlate with FGFR protein or RNA expression. In sensitive cell lines, AZD4547 inhibited p-MAPK in a time dependent manner. Significant radiosensitization with AZD4547 was observed in cell lines that were sensitive to AZD4547. The mechanism underlying these effects appear to be multifactorial involving inhibition of the MTOR pathway and subsequent enhancement of autophagy and activation of apoptotic pathways. Significant tumor growth delay was observed when AZD4547 was combined with radiation compared to radiation or drug alone in a FGFR-expressing HNSCC cell line xenograft and PDX. CONCLUSIONS These findings suggest that AZD4547 can augment the response of radiation in FGFR-expressing HNSCC in vivo model systems. FGFR1 and FGFR2 may prove worthy targets for radiosensitization in HNSCC clinical investigations. The pejerrey is an atherinopsid species from South America that presents a combination of genotypic and environmental (temperature-dependent) sex determination whereby low and high temperatures induce feminization and masculinization, respectively. Masculinization involves a heat-induced stress response leading to increased circulating cortisol and androgens. We tested whether crowding would elicit a similar response as high temperature and affect the sex ratios of pejerrey. Larvae with XX and XY genotypes were reared at 15, 62 and 250 larvae/L in 0.4, 1.6, and 6.4?L containers during a period considered critical for sex determination at 25?°C, a mixed-sex promoting temperature. Fish were analysed at 3-7?weeks for whole-body cortisol and 11-ketotestosterone (11-KT) titer and hydroxy-steroid dehydrogenase (hsd11b2) mRNA transcript abundance, and after completion of gonadal sex differentiation (10-14?weeks) for determination of phenotypic and genotypic sex mismatches. Crowding was associated with depressed growth, higher cortisol and 11-KT titers, increased hsd11b2 transcription, and increased frequency of masculinization compared to intermediate and/or low rearing densities. Perceived crowding (by rearing in containers with mirror-finish, reflecting walls) also caused masculinization. These results suggest the possibility that other environmental factors besides temperature can also affect sex determination in pejerrey and that a stress response leading to increased cortisol and androgen levels, which is potentially perceived by the brain, may be a common feature among different forms of environmental sex determination in this species. OBJECTIVES Ionic liquids have shown potential for applications as antimicrobials. Their antimicrobial activity has been shown to be higher against Gram-positive than Gram-negative bacteria, suggesting a protective role for the outer membrane of Gram-negative microorganisms. Colistin is a last-resort antibiotic often used for treating infections sustained by multi-drug resistant Gram-negative bacteria. Colistin interacts with the bacterial lipopolysaccharide, thus altering the structure and increasing the permeability of the outer membrane. The aim of this study was to investigate the interaction between colistin and the ionic liquids 1-methyl-3-dodecylimidazolium bromide, 1-dodecyl-1-methylpyrrolidinium bromide, and 1-dodecyl-1-methylpiperidinium bromide against Gram-negative bacteria of clinical importance such asEscherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, and Acinetobacter baumannii. METHODS The interaction between colistin and ionic liquids against Gram-negative bacteria was evaluated by the checkerboard assay. Bacterial killing assays againstP. aeruginosa were carried out to assess whether the synergistic combinations were bactericidal. RESULTS The results of checkerboard assays showed that all three ionic liquids interacted synergistically with colistin againstK. pneumoniae, P. aeruginosa, and A. baumannii but not against Escherichia coli, which resulted more sensitive to all three ionic liquids compared to the other tested species. The synergistic combinations showed no hemolytic activity. Bacterial killing assays showed that the synergistic effect between colistin and each one of the three tested ionic liquids against P. aeruginosa was bactericidal. CONCLUSION Overall, the results obtained suggest that colistin and ionic liquids might be used in combination for possible applications to combat infections sustained by multi-drug resistant Gram-negative bacteria.